Tiny circles of DNA that defy the accepted laws of genetics are key drivers of cancer formation, according to an international study led by researchers at Stanford Medicine.

The circles, known as extrachromosomal DNA or ecDNA, often harbor cancer-associated genes called oncogenes. Because they can exist in large numbers in a cell, they deliver a super-charged growth signal that can override a cell's natural programming. They also contain genes likely to dampen the immune system's response to a nascent cancer, the researchers found.

Previous research had suggested that the circles, which are widespread in human cancers but rarely found in healthy cells, primarily arise in advanced tumors as the abnormal cells increasingly botch the intricate steps required to copy their DNA before each cell division. But the new study shows that the roly-poly circles can be found even in precancerous cells — and their presence jump-starts a cancerous transformation. Blocking their formation, or their effect on the cells that carry them, might stop cancers from developing, the researchers believe.

This study has profound implications for our understanding of ecDNA in tumor development. It shows the power and diversity of ecDNA as a fundamental process in cancer. It has implications for early diagnosis of precancers that put patients at risk, and it highlights the potential for earlier intervention as treatments are developed." 

Paul Mischel, MD, professor of pathology

Mischel is one of six senior authors of the research, which was published April 12 in Nature. Howard Chang, MD, PhD, professor of genetics and the Virginia and D.K. Ludwig Professor in Cancer Research, is also a senior author. Other senior authors include senior staff scientist Thomas Paulson, PhD, from Seattle's Fred Hutchison Cancer Center; assistant professor of pediatrics Sihan Wu, PhD, assistant professor at Children's Medical Center Research Institute at the University of Texas Southwestern Medical Center; professor of computer science and engineering Vineet Bafna, PhD, from UC San Diego; and professor of cancer prevention and director of the Early Cancer Institute Rebecca Fitzgerald, MD, from the University of Cambridge.  

"People with ecDNA in their precancerous cells are 20 to 30 times more likely than others to develop cancer," Chang said. "This is a huge increase, and it means we really need to pay attention to this. Because we also found that some ecDNAs carry genes that affect the immune system, it suggests that they may also promote early immune escape."

Deciphering ecDNA's role in cancer was one of four Cancer Grand Challenges awarded by the National Cancer Institute and Cancer Research UK in 2022. The grand challenges program was launched to bring together researchers from around the world to tackle complex research topics too daunting for any one group. Mischel was awarded $25 million to lead a team of international researchers to learn more about the circles. But first they had to jettison some key genetic principles that have guided the field for nearly 200 years.

Source:

Journal reference:

Luebeck, J., et al. (2023). Extrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus. Nature. doi.org/10.1038/s41586-023-05937-5.